In this section, we mainly focus on delineating the roles of the tumor cell-associated immune checkpoint molecules beyond immune evasion, such as PD-L1, PD-1, B7-H3, B7-H4, LILRB1, LILRB2, TIM3, CD47, CD137, and CD70.Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockade, have led to therapeutic breakthrough in patients with advanced malignancy, covering the lung, breast, gastrointestinal, head and neck, urinary system, lymphoma, and solid tumor harboring MSI/dMMR. In certain cancer types, the expression level of immune checkpoint molecule will be required if the immune-based approaches are considered, especially the PD-L1 expression. However, in other types, survival benefit has been proven regardless of PD-L1 expression. It raises a question of how to select patients for immune therapy and whether the expression of immune checkpoint molecules will be optimal biomarkers. Before answering this question, a comprehensive map for the expression of immune checkpoint molecules is needed. In this chapter, we describe our current knowledge on the spatiotemporal changes in the expression of checkpoint molecules. We discuss the different frequencies of expression depending on tumor types and stages, the different patterns between primary and metastatic tumors, as well as the change of expression before and after treatment. The expression of PD-L1 has been most studied, but the threshold that separate "positive" and "negative" PD-L1 expressions and the consistency of testing platform remain under debate. Better understanding on the tumor microenvironment and expression of checkpoint molecules will help to identify patients who will benefit from checkpoint blockade therapy.Immunotherapy with checkpoint inhibitor has been successfully applied in treatment for multiple cancer types, especially for patients at advanced stage. However, response rate of this promising therapy is low, thus requiring biomarkers for precise medication to reduce the ineffective treatment. With multiple retrospective clinical studies, more and more candidate prognostic factors have been identified with possible mechanic explanation, including the basic clinical characteristics (e.g., age and gender), molecular features (e.g., PD-L1 expression and tumor mutation burden). After validation in independent patient cohorts with large sample size, several markers have been approved as companion biomarkers. However, validation and combinations of all the possible candidate biomarkers are still challenging to predict the treatment outcomes. In this chapter, we will summarize and introduce the prognostic factors and biomarkers for checkpoint inhibitor-based immunotherapy.Immune checkpoint blockade (ICB) therapy has become a promising way of overcoming cancers, whereas the therapy can induce immunopathology due to the disruption of the immune homeostasis. These adverse events caused by ICB are named as immune-related adverse events (irAEs), which can be severe and life-threaten. Understanding the mechanisms and managements of irAEs is critical for improving the efficacy of immune checkpoint therapy. Immune-related adverse events can occur on various organs, and gastrointestinal tract has the highest rate for severe irAEs. Accumulated evidences indicate the ability of the gut microbiota in regulating the response to immune checkpoint therapy, but the function of microbiota in irAEs remains unclear. T cells, including functional subsets Th17 T cells and regulatory T (Treg) cells, play significant roles in determining the inflammatory microenvironment. The gut immune tolerance toward dietary antigens and commensals, and anti-inflammatory function in intestines are maintained mainly by Treg cells. Furthermore, tissue residency of functional T cells depends on the homing/trafficking to the locations of inflammation. Here, we review the role of microbiota and the interaction between microbiota and intestinal Treg cells in irAEs, and discuss the function of gut-trafficking blockade antibodies in the context of ICB therapy.Immune checkpoint blockades (ICBs), as a major breakthrough in cancer immunotherapy, target CTLA-4 and the PD-1/PD-L1 axis and reinvigorate anti-tumor activities by disrupting co-inhibitory T-cell signaling. With unprecedented performance in clinical trials, ICBs have been approved by FDA for the treatment of malignancies such as melanoma, non-small-cell lung cancer, colorectal cancer, and hepatocellular carcinoma. However, while ICBs are revolutionizing therapeutic algorithms for cancers, the frequently observed innate, adaptive or acquired drug resistance remains an inevitable obstacle to a durable antitumor activity, thus leading to non-response or tumor relapse. Researches have shown that resistance could occur at each stage of the tumor's immune responses. From the current understanding, the molecular mechanisms for the resistance of ICB can be categorized into the following aspects 1. Tumor-derived mechanism, 2. https://www.selleckchem.com/products/shp099-dihydrochloride.html T cell-based mechanism, and 3. Tumor microenvironment-determined resistance. In order to overcome resistance, potential therapeutic strategies include enhancing antigen procession and presentation, reinforcing the activity and infiltration of T cells, and destroying immunosuppression microenvironment. In future, determining the driving factors behind ICB resistance by tools of precision medicine may maximize clinical benefits from ICBs. Moreover, efforts in individualized dosing, intermittent administration and/or combinatory regimens have opened new directions for overcoming ICB resistance.The first generation of immune checkpoint inhibitors (ICIs) including anti-CTLA-4 and anti-PD-1/anti-PD-L1 has achieved profound and great success. Till 2019 Q1, there are nine ICIs landing the oncology market Ipilimumab (anti-CTLA-4, Bristol-Myers Squibb), Nivolumab (anti-PD-1, Bristol-Myers Squibb), Pembrolizumab (anti-PD-1, Merck), Atezolizumab (anti-PD-L1, Roche/Genentech), Durvalumab (anti-PD-L1, Astra Zeneca), Tremelimumab (anti-CTLA-4, Astra Zeneca), Cemiplimab (anti-PD-1, Sanofi/Regeneron), Toripalimab (anti-PD-1, Junshi), and Sintilimab (anti-PD-1, Innovent), which have covered the majority of hematologic and solid malignancies' indication. Beyond the considerable benefits for the patients, frustrated boundary still exists limited response rate in monotherapy in late-stage population, poor effectiveness in neoplasms with immune desert and immune excluded types, and immune-related toxicities, some are life-threatened and with higher incidence in I-O combination regiment. Moreover, clinicians observed some cases switching to progression after achieving partial or complete response, indicating treatment failure or drug resistance.